All pregnant women were withdrawn from the study. 4 women had miscarriages, all in the active arm. After 2 years there were 21 more pregnancies with 2 miscarriages – evenly spread over active and placebo groups.

Women with infertility were included in this study however data from women who conceived were excluded. This may have led to an underestimation of treatment effect (type 1 error).

Primary outcome for participants with amenorrhoea: at least one spontaneous menses.

Oligomenorrhoeic subgroup - clinical outcomes were significantly improved in the treatment arm at 82% compared to 45% in placebo arm P = 0.021. When the amenorrheic group were included in analysis, differences were not significant p = 0.19.

Diagnosis for anovulatory amenorrhoea is not well described. Non-statistically significant take home baby rates were complicated by insufficient sample size. 366 patients are required to have a 95% chance, as significant at the 5% level, an increase in take home baby rates from 6% in the placebo group to 18% in the experimental group. The authors conclude that this preparation may be useful if given 3–6 months, yet they only tested for 3 months.

1.oligomenorrhoea, n = 37

For progesterone <1 ng/mL: an increase to >5 ng/mL at the end of 3rd cycle

Randomised controlled trial using with an active control arm for comparative effectiveness. One menstrual cycle.

147 women aged less than 35 years with un-explained infertility and recurrent clomiphene resistance for ovulation induction. Anovulatory participants were excluded (n = 28). Anovulation was diagnosed by serum oestradiol < 200 ng/ml and absence of a dominant ovarian follicle on day 9 of the menstrual cycle. Complete data sets available for 119 women.

All women received Clomiphene citrate (clomiphene) 150 mg on menstrual cycle days 3–7. A randomised group also took Cimicifuga racemosa 20 mg per day between days 1–12. Cimicifuga racemosa described as ‘phytoestrogens’ was provided in the commercial preparation Klimadynon®, manufactured by Norica in Germany. A trigger injection (human chorionic gonadotropin, 10 000 IU) and timed intercourse was recommended when a dominant follicle > 17 mm was observed.

Pregnancy rate measured as increasing serum human chorionic gonadotropin (HCG) over two days. Clinical pregnancy defined as detection of gestational sac with embryonic heart-beat. Endometrial thickness measured by ultrasound concurrent with follicle maturation monitoring. Number of days to ovulation (trigger injection) Serum concentration for FSH oestradiol and LH. Luteal progesterone measured on days 21–23 of the menstrual cycle. Miscarriage and multiple pregnancy rates.

Pregnancy rate in clomiphene alone group was 20.3% and 43.3% in the clomiphene plus Cimicifuga racemosa group (P < 0.01). Clinical pregnancy rate in the combination group was 36.7% versus 13.6% in the clomiphene alone group (P < 0.01). Endometrial thickness in combination group was 8.9 (±1.4) versus 7.5 (±1.3) (p < 0.001). Days to ovulation in clomiphene alone group was 13.0 ± 1.1 and in the clomiphene plus Cimicifuga racemosa group 14.2 ± 1.3 (n.s.). Luteal progesterone peak (ng/ml) in combination group was 13.3 (±3.1) versus 9.3 (±2.0) in clomiphene alone group (p < 0.01). All other hormone measures were not significantly different

No detailed current baseline criteria for other causes of infertility. Confounding factors include current male fertility status. This may have caused an imbalance between the two groups. There is no description of the distribution of excluded (anovulatory) participants between groups.

Randomised controlled trial with an active control group. Comparative effectiveness trial for ovulation induction in women with PCOS. Three menstrual cycles.

Women aged 21–27 with primary or secondary infertility. Diagnosis of PCOS by ultrasound and clinical history (n = 100). Gynaecology outpatient clinic. Two groups. Group one (n = 50) received Clomiphene citrate 100 mg days 2–7 of the menstrual cycle; group two (n = 50) received 20 mg Cimicifuga racemosa for days 2–12 of the menstrual cycle.

Pregnancy rates were 33 out of 192 cycles (17.2%) for the clomiphene alone group and 71 out of 204 cycles (34.8%) for the clomiphene plus Cimicifuga racemosa group.

Non-blinding compromised the internal validity of the findings in this study. Confounding variables include variations in participant’s and clinicians attitudes and may have led to differences which were unaccounted for between the two groups. However the outcomes are objective with a statistically powered sample size.

Serum LH was 8.0 (±0.9) in the clomiphene group and 5.7 (±0.9) in the clomiphene plus Cimicifuga racemosa group (p < 0.001) and oestradiol was 228.3 (±30.2) in the clomiphene alone group and 299.5 (±38.9) \in the clomiphene plus Cimicifuga racemosa group (p = 0.01)

4. Pregnancy outcomes for early miscarriage.

Miscarriages were 5 out of 192 cycles in the clomiphene group and 6 out of 204 cycles in the clomiphene plus Cimicifuga racemosa group (n.s.).

Improved insulin sensitivity (QUICKI) in the treatment group. 0.35 to 0.38, (7.7%) p < 0.03. Insulin resistance (HOMO-IR) significantly reduced in treatment group 2.57 to 1.43 (44.5%) p < 0.03. Controls no change insulin sensitivity or insulin resistance. No change in either group for BMI, testosterone and oestradiol. Differences between Cinnamomum cassia group and normal weight and ovulatory controls were not significant. (P < 0.17). No reported adverse reactions.

Small pilot study, the authors report that larger studies are required to confirm findings. Small sample size may explain non-significant comparison with normal weight and ovulating women. Reproductive outcomes were unchanged in this study however the duration of the study was insufficient to demonstrate reproductive changes.